Liposomes are spherical, lipid bilayer nanocapsules (20 to >1000 nm diameter) that are becoming increasingly important as transport vehicles for delivering medicinal agents. The potential advantages of the nano-encapsulation of diagnostic or therapeutic compounds--reduced toxicity, improved stability, controlled bioavailability, and selectively localization--prompt intense basic and applied research. Treatment of cancers has benefited from nanoencapsulation and presently several commercial liposomal formulations containing therapeutic agents are available and others are at various investigational stages. Despite major advances, significant obstacles impede the application of liposomal delivery generally, and its use in cancer treatment specifically. Three of these problems are addressed by these proposed pilot studies, which seek to further the basic chemical understanding of the underlying phenomena: (1) engineering liposome stability within parameters that are compatible with delivery properties, (2) directing nanocapsule accumulation in diseased tissues, and (3) devising mechanisms that release medicinal compounds once accumulation at targeted tissues has occurred. Studies in specific aim 1 will address the first problem by employing novel amino acid-based lipid analogs to modify liposome thermal and pH stabilities. Preliminary studies have already demonstrated that a prototype lipid analog is capable of liposome incorporation and enhances liposome stability in acidic environments. Proposed synthetic studies will lead to the preparation of structurally diverse lipid analogs for examining the cytotoxicity of these materials and for additional liposome stability studies. To investigate the second problem, we will develop chemical transformations that attach target-seeking features to the liposome surface. In pursuit of the third aim, studies will be conducted on novel chemical mechanisms that will increase the leakage of liposome contents. The long-term goal of this project is to enhance liposome properties for medicinal agent delivery by exploiting novel fatty amino acid analogs invented in our laboratory. The achievement of the goals of this application may lead to the development of medicinal agent delivery nanocapsules that impart improved effectiveness and decreased toxicity. This would significantly improve treatment outcomes and diminish the negative side effects associated with the toxicities of therapeutic drugs. [unreadable] [unreadable] [unreadable]